Submissions for variant NM_000143.4(FH):c.521C>G (p.Pro174Arg)

gnomAD frequency: 0.00003  dbSNP: rs199822819

Total submissions: 16

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000078149	SCV000109987	pathogenic	not provided	2013-03-06	criteria provided, single submitter	clinical testing
Invitae	RCV000078149	SCV000283674	pathogenic	not provided	2024-01-29	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 174 of the FH protein (p.Pro174Arg). This variant is present in population databases (rs199822819, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive fumarase deficiency (PMID: 12761039, 16575891, 22069215). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 392C>G (Pro131Arg). ClinVar contains an entry for this variant (Variation ID: 29705). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FH protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects FH function (PMID: 12761039, 16575891, 22595425). For these reasons, this variant has been classified as Pathogenic.
Illumina Laboratory Services, Illumina	RCV000022554	SCV000356713	likely pathogenic	Fumarase deficiency	2017-04-27	criteria provided, single submitter	clinical testing	The FH c.521C>G (p.Pro174Arg) missense variant has been reported in three studies in which it is found in a compound heterozygous state in four individuals with fumarate hydratase, two of whom were siblings with a severe phenotype who carried the p.Pro174Arg variant and a deletion in the FH gene (Alam et al. 2003; Mroch et al. 2012; Kimonis et al. 2012). Control data are unavailable for the p.Pro174Arg variant, which is reported at a frequency of 0.00045 in the African American population of the Exome Sequencing Project but this is based on two alleles only in a region of good sequencing coverage so the variant is presumed rare. Functional studies in patient skin fibroblasts and cells lines showed that the variant resulted in between 13 - 25% fumarase activity compared to controls (Alam et al. 2003; Kimonis et al. 2012). Based on the evidence the p.Pro174Arg variant is classified as likely pathogenic for fumarate hydratase deficiency. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population.
GeneDx	RCV000078149	SCV000516751	pathogenic	not provided	2023-07-28	criteria provided, single submitter	clinical testing	Observed multiple times with a pathogenic variant on the opposite allele (in trans) and in the homozygous state in unrelated patients with fumarate hydratase deficiency, including those whose lymphocytes demonstrated decreased fumarate hydratase activity (Alam et al., 2003; Pollard et al., 2005; Zeng et al., 2006; Kimonis et al., 2012; Mroch et al., 2012; Ryder et al., 2018); Heterozygous individuals in the literature and at GeneDx with this variant have not been reported to have features of hereditary leiomyomatosis and renal cell cancer (HLRCC); therefore, its association with HLRCC is uncertain (Zeng et al., 2006; Mroch et al., 2012); Published functional studies demonstrate reduced rate of conversion of fumarate and malate in vitro (Wilde et al., 2023); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Also known as p.Pro131Arg; This variant is associated with the following publications: (PMID: 29909963, 20549362, 16029320, 16575891, 26580448, 31831373, 25637381, 21445611, 22069215, 22595425, 12761039, 15987702, 29052812, 16237213, 29086383, 11865300, 32191290, 34308104, 37255402)
Ambry Genetics	RCV000492836	SCV000581681	pathogenic	Hereditary cancer-predisposing syndrome	2022-12-08	criteria provided, single submitter	clinical testing	The p.P174R pathogenic mutation (also known as c.521C>G), located in coding exon 4 of the FH gene, results from a C to G substitution at nucleotide position 521. The proline at codon 174 is replaced by arginine, an amino acid with dissimilar properties. This alteration has been observed in multiple individuals with fumarate hydratase (FH) deficiency in conjunction with another mutation in trans or in a homozygous state (Alam NA et al. Hum. Mol. Genet. 2003 Jun;12:1241-52; Zeng WQ et al. Am. J. Med. Genet. A. 2006 May;140:1004-9; Mroch AR et al. Am. J. Med. Genet. A. 2012 Jan;158A:155-8; Ryder B et al. JIMD Rep 2018 Oct;40:77-83). In addition, patients with FH deficiency and this alteration have shown reduced enzyme activity (13-36%) relative to controls (Pollard PJ et al. Hum. Mol. Genet. 2005 Aug;14:2231-9; Zeng WQ et al. Am. J. Med. Genet. A. 2006 May;140:1004-9; Kimonis VE et al. Mol. Genet. Metab. 2012 Sep;107:241-2). Of note, this alteration is also designated as p.P131R in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, p.P174R is classified as a pathogenic mutation in association with FH deficiency; however, this is not considered a risk factor for HLRCC.
Academic Department of Medical Genetics, University of Cambridge	RCV000492836	SCV000992190	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-01-26	criteria provided, single submitter	research	Application of AMCG guidelines 2015. Used other ClinVar submission evidence where relevant. Loss of heterozygosity in tumours or immunohistochemistry abnormalities considered functional evidence of pathogenicity.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000078149	SCV002048740	pathogenic	not provided	2020-12-05	criteria provided, single submitter	clinical testing
Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	RCV003335052	SCV004046437	pathogenic	FH-Related Disorders		criteria provided, single submitter	clinical testing	This variant has been previously reported as a compound heterozygous and homozygous change in patients with fumarase deficiency (PMID: 12761039, 22069215, 16575891). Functional studies showed that the c.521C>G (p.Pro174Arg) variant resulted in an increase in excretion of fumaric acid and reduced fumarase activity in fibroblast cells (PMID: 22595425, 12761039, 16575891). The c.521C>G (p.Pro174Arg) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.002% (7/282696) and is absent in the homozygous state, thus is presumed to be rare. The c.521C>G (p.Pro174Arg) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Based on the available evidence, the c.521C>G (p.Pro174Arg) variant is classified as Pathogenic.
Baylor Genetics	RCV000022554	SCV004197294	likely pathogenic	Fumarase deficiency	2023-10-29	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000078149	SCV004218884	pathogenic	not provided	2022-06-24	criteria provided, single submitter	clinical testing	The frequency of this variant in the general population, 0.000054 (7/129060 chromosomes, http://gnomad.broadinstitute.org), is consistent with pathogenicity. This variant has been detected in individuals with fumarase deficiency, who were compound heterozygous and homozygous for the variant (PMID: 22069215 (2012), 16575891 (2006), 12761039 (2003)). Additionally, the variant was shown to result in reduced enzyme activity (PMID: 12761039 (2003)). Based on the available information, this variant is classified as pathogenic.
OMIM	RCV000022554	SCV000043843	pathogenic	Fumarase deficiency	2012-01-01	no assertion criteria provided	literature only
CSER _CC_NCGL, University of Washington	RCV000022554	SCV000190212	likely benign	Fumarase deficiency	2014-06-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000078149	SCV001739661	likely pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000078149	SCV001955222	pathogenic	not provided		no assertion criteria provided	clinical testing
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV000353057	SCV002012378	uncertain significance	Hereditary leiomyomatosis and renal cell cancer	2021-08-19	flagged submission	clinical testing	The FH c.521C>G (p.Pro174Arg) missense change has a maximum subpopulation frequency of 0.0054% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/variant/1-241675301-G-C). Seven of seven in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional studies which interrogate this variant alone. This variant has been reported to be in trans with pathogenic variants in FH in individuals affected with autosomal recessive fumarase deficiency (PMID: 12761039, 22069215) and has been reported as homozygous in an individual with mild fumarase deficiency (PMID: 16575891). To our knowledge, this variant has not been reported in individuals with hereditary leiomyomatosis and renal cell cancer (HLRCC) and individuals identified to be heterozygous for this variant did not have a personal or family history of HLRCC (PMID: 12761039, 16575891, 22069215). This variant is also known as c.392C>G (p.Pro131Arg) in the literature. In summary, this variant meets criteria to be classified as pathogenic with respect to autosomal recessive FH deficiency, and of uncertain significance with respect to autosomal dominant HLRCC based on the ACMG/AMP criteria: PP3.
GenomeConnect - Invitae Patient Insights Network	RCV003483435	SCV004228558	not provided	Fumarase deficiency; Hereditary leiomyomatosis and renal cell cancer		no assertion provided	phenotyping only	Variant interpreted as Pathogenic and reported on 05-13-2019 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.